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Absent intestinal response to calciferols in hereditary resistance to 1,25-dihydroxyvitamin D: documentation and effective therapy with high dose intravenous calcium infusions.

We describe a patient with an absent intestinal response to 1,25-dihydroxyvitamin D [1,25-(OH)2D] and the beneficial effects of treatment with high dose iv calcium infusion. The patient presented with severe rickets despite therapy with extraordinarily high doses of 1 alpha-hydroxyvitamin D3 or 1,25-(OH)2D3. Unidirectional intestinal fractional calcium absorption when he was not treated with any calciferol was 14% (normal, 20-70%), as measured with stable calcium isotopes; no increase in calcium absorption occurred when serum 1,25-(OH)2D levels were more than 50-fold elevated. Cultured skin fibroblasts contained no detectable 25-hydroxyvitamin D3-24-hydroxylase activity in response to 1,25-(OH)2D3 (10(-9)-10(-6) mol/L). High dose iv calcium infusions and oral phosphorus supplementation for 135 days improved or normalized biochemical parameters and resulted in radiographic healing of the rachitic lesions. We conclude that 1) this patient had no response to 1,25-(OH)2D3 in vivo and in vitro; 2) long term parenteral calcium infusions were effective therapy in managing the patient's severe resistance to 1,25-(OH)2D; and 3) stable calcium isotopes are useful for measuring low levels of fractional calcium absorption.

Alkaline Phosphatase↗

Effects of development on techniques for calcium stable isotope studies in children.

We evaluated the effects of age and pubertal status on the tracer excess measured in urine samples collected during the 120 h after the oral and intravenous administration of calcium stable isotopes to 90 children (16 preterm infants and 74 females aged 4.9-16.8 years). Analysis of subjects shows differences in distribution volume and fractional absorption of calcium based on developmental status, with four separate groups being identified. These are: (i) premature infants; (ii) prepubertal girls (Tanner stage 1); (iii) early pubertal girls (Tanner states 2-3); and (iv) late pubertal girls (Tanner stages 4-5). Identification of groups in this fashion allows for adequate dosing in calcium stable isotope studies, with the minimum dose being given to achieve an increase in urinary isotopic content consistent with the precision of the analytical equipment.

Adolescent↗

Calcium absorption in Crohn's disease.

Calcium absorption and endogenous loss of calcium were measured in a group of patients with Crohn's disease, using a simultaneous metabolic balance and calcium isotope regimen. Calcium malabsorption resulting in negative calcium balance was found in only 4 of 31 patients with Crohn's disease. No elevation of endogenous fecal calcium or total secreted intestinal calcium was observed in 10 patients studied, regardless of the level of net or true calcium absorption. Correlation between calcium balance and serum protein loss was observed, but no association was noted with intestinal fat excretion, d-xylose absorption, bacterial colonization of the jejunum, or glucocorticosteroid therapy. The results indicate that in this group of patients with Crohn's disease involving different areas of the intestine, calcium malabsorption occurred infrequently and that the levels of calcium excretion correlated best with enteric protein loss.

Adolescent↗

Chromaffin cell calcium channel kinetics measured isotopically through fast calcium, strontium, and barium fluxes.

Fast Ca2+ uptake into K+-depolarized cultured bovine adrenal chromaffin cells has been isotopically measured in a time scale of 1-10 s. Depolarized cells retained as much as 80-fold 45Ca2+ taken up by resting cells; Ca2+ was not taken up by fibroblasts or endothelial-like cells. Because Ca2+ entry was inhibited by inorganic (La3+, Co2+, Mg2+) and organic (nifedipine) Ca2+ channel antagonists and enhanced by the Ca2+ channel activator Bay-K-8644, it seems clear that Ca2+ gains access to the chromaffin cell cytosol mainly through specific voltage-dependent Ca2+ channels. Ca2+ uptake evoked by 59 mM K+ was linear during the first 5 s of stimulation and continued to rise at a much slower rate up to 60 s. The rate of Ca2+ entry became steeper as the external [Ca2+] increased; initial rates of Ca2+ uptake varied from 0.06 fmol/cells . s at 0.125 mM Ca2+ to 2.85 fmol/cell . s at 7.5 mM Ca2+. The early 90Sr2+ uptake was linear but faster than Ca2+ uptake and later on was also saturated; 133Ba2+ was taken up still at a much faster rate and was linear for the entire depolarization period (2-60 s). Increased [K+] gradually depolarized chromaffin cells; Ca2+ and Sr2+ uptakes were not apparent below 30 mM K+ but were linear for 30 to 60 mM K+. In contrast, substantial Ba2+ uptake was seen even in K+-free solutions; and in 5.9 mM K+, Ba2+ uptake was as high as Ca2+ uptake obtained in 60 mM K+. Five to ten-second pulses of 45Ca2+, 90Sr2+, or 133Ba2+ given at different times after pre-depolarization of chromaffin cells served to analyze the kinetics of inactivation of the rates of entry of each divalent cation. Inactivation of Ca2+ uptake was faster than Sr2+, and Ba2+ uptake inactivated very little. Neither voltage changes nor Ca2+ ions passing through the channels seems to cause their inactivation; however, experiments aimed to manipulate the levels of internal Ca2+ using the cell-permeable chelator Quin-2 or the ionophore A23187 strongly suggest that intracellular Ca2+ levels determine the rates of inactivation of these channels.

Adrenal Gland Neoplasms↗

Plasma kinetics of magnesium and calcium stable isotope tracers in a human subject after simultaneous oral ingestion of 25Mg and 44Ca determined by thermal ionization mass spectrometry.

The plasma concentrations of stable isotope tracers of magnesium (25Mg) and calcium (44Ca) were determined during a 50 h period, after simultaneous oral tracer ingestion in an adult man. The measurements were performed by magnetic sector field mass spectrometry using surface ionization ion sources. The data were used to evaluate the potential of this method in long-term kinetic studies. It is concluded that under the experimental conditions specified, the isotopic tracers will be detectable in blood plasma with sufficient precision and accuracy for approximately 600 h after oral ingestion. The differences in the plasma concentration curves of 25Mg and 44Ca were analysed by means of the convolution integral method. These differences indicate inhomogeneities in the distribution of absorption activity relative to magnesium and calcium within the upper small intestine.

Administration, Oral↗

Recent studies of human calcium metabolism using stable isotopic tracers.

Stable isotopes of calcium are used safely as tracers for calcium in human populations ranging in age from infants to postmenopausal women. Thermal ionization mass spectrometry is used to measure calcium isotope ratios with relative accuracies of about 1% for natural abundance ratios at precisions of about 1% relative to the mean. Perturbations of natural abundance ratios are determined for the calcium in blood, urine, and feces with a limit of detection of about 2 delta % excess. The mathematical rationale for clinical studies of fractional absorption of dietary calcium and the kinetics of calcium's internal distribution are presented.

Animals↗

A stable tracer technique for calcium metabolism studies.

A tracer technique using the stable isotope calcium-48 was developed to facilitate studies of human calcium metabolism. Small samples of 1 ml serum were used. Calcium levels were determined with good precision using neutron-activation analysis after pre-concentration of the serum calcium by oxalate precipitation. The method has sufficient sensitivity to detect induced dilutions of the tracer by administering other less costly isotopes of calcium. The ability to utilize small volumes of sample is of direct benefit to paediatric metabolism research. The favourable results obtained for two calcium loading tests demonstrate the applicability of the technique to intestinal absorption studies.

Calcium↗

Calcium metabolism in adult outpatients with epilepsy receiving long-term anticonvulsant therapy.

Long-term anticonvulsant drug therapy may lead to abnormalities of calcium metabolism resulting in osteomalacia. The prevalence and severity of altered calcium metabolism was studied in an adult outpatient population of persons with epilepsy receiving anticonvulsant therapy for a minimum of 2 years. Assessment of calcium metabolism was based on serum concentrations of calcium, phosphorus, alkaline phosphatase and 25-hydroxycholecalciferol and of plasma parathyroid hormone, intestinal absorption of isotopic calcium and skeletal bone mineral mass as determined by in vivo neutron activation or x-ray photodensitometry.Thirty-nine patients who had been receiving anticonvulsant therapy for an average of 20 years were studied; none had clinical evidence of metabolic bone disease. Decreased serum calcium concentration was noted in 10%, decreased serum phosphorus concentration in 10% and elevated serum alkaline phosphatase concentration in 44%. The mean serum 25-hydroxycholecalciferol concentration was significantly lower (P < 0.001) than in a control group (11.6 v. 19.6 mg/mL). None of 18 patients studied had an increased plasma concentration of parathyroid hormone, and only 1 of 17 patients had decreased intestinal absorption of isotopic calcium. Bone mineral mass was decreased in 44% of 32 patients studied.It was concluded that long-term treatment with anticonvulsant drugs leads to mild abnormalities of calcium metabolism and decreased bone mineral mass in a substantial percentage of adult outpatients with epilepsy. These abnormalities probably predispose the patients to the development of clinically significant metabolic bone disease.

Adult↗

Bone calcium turnover during pregnancy and lactation in women with low calcium diets is associated with calcium intake and circulating insulin-like growth factor 1 concentrations.

BACKGROUND: Few data exist on longitudinal changes in bone calcium turnover rates across pregnancy and lactation. OBJECTIVE: Our aim was to characterize calcium kinetic variables and predictors of these changes across pregnancy and early lactation in women with low calcium intakes. DESIGN: Stable calcium isotopes were administered to 10 Brazilian women during early pregnancy (EP; weeks 10-12 of gestation), late pregnancy (LP; weeks 34-36 of gestation), and early lactation (EL; 7-8 wk postpartum). Multicompartmental modeling was used to assess the rates of bone calcium turnover in relation to calcium intakes and circulating concentrations of parathyroid hormone (PTH), insulin-like growth factor 1, and 1,25-dihydroxyvitamin D. RESULTS: Rates of bone calcium deposition increased significantly from EP to LP (P = 0.001) and were significantly associated with serum PTH during LP (P < or = 0.01). Rates of bone calcium resorption were also higher during LP and EL than during EP (P < or = 0.01) and were associated with both PTH (P < or = 0.01) and IGF-1 (P < or = 0.05) during LP but not during EL. Net balance in bone calcium turnover was positively associated with dietary calcium during EP (P < or = 0.01), LP (P < or = 0.01), and EL (P < or = 0.01). The mean (+/-SD) calcium intake was 463 +/- 182 mg/d and, in combination with insulin-like growth factor 1, explained 68-94% of the variability in net bone calcium balance during pregnancy and lactation. CONCLUSIONS: Net deficits in bone calcium balance occurred during pregnancy and lactation. Increased dietary calcium intake was associated with improved calcium balance; therefore, greater calcium intakes may minimize bone loss across pregnancy and lactation in women with habitual intakes of <500 mg calcium/d.

Adult↗